Two of the most consistent biologic abnormalities found during depression are excess production of cortisol and decreased latency to rapid-eye movement (REM) sleep. We are employing a pharmacologic challenge strategy to attempt to elicit similar abnormalities in well state patients off medications. The muscarinic cholinergic agonist arecoline is being used to provoke REM in sleeping subjects. Thirty patients and 21 controls have participated in this ongoing project. The serotonin precursor tryptophan and the opiate antagonist naloxone have been used to probe cortisol secretion. Dose-response studies have been completed. Both agents provoke significant increases in cortisol. Patient versus control comparisons are in progress. Beta endorphin levels have been reported elevated in affective patients, both at base-line and in response to cholinergic stimulation. We have demonstrated beta endorphin elevations in response to naloxone and to high doses of arecoline and tryptophan. In the latter two paradigms beta endorphin elevation appears related to a stress response. The serotonin receptor blocker metergoline appears to block the dextroamphetamine-induced rise in cortisol in preliminary data analysis. This observation, if substantiated in further testing, would conclude our neurochemical analysis of amphetamine effects.